Compositions and methods for alleviating impaired mental function, memory loss and reducing recovery time in anaesthetized mammals

Abstract

Composition and methods of alleviating impaired mental function and memory loss in mammals and reducing the recovery time from anaesthesia in age mammals, comprising treating the mammal with a non-toxic, enhancing effective amount of a cell membrane permeant calcium buffer. The buffer is preferably a calcium ion chelating agent having a KD selected from the range 1x10-4 to 1x10-8 Molar and being essentially calcium ion-selective over other metal ions. A most preferred buffer is BAPTA-AM.

Description

This invention relates to methods of alleviating impaired mental function, memory loss and reducing recovery time in anaesthetized mammals using a cell membrane permeant calcium buffer, said calcium buffers per se, pharmaceutical compositions comprising said calcium buffers and methods for the preparation of said pharmaceutical compositions.Progressive learning and memory impairment occurs during the normal course of aging (1,2,3). A strong functional link has been established between the hippocampal region of the brain and learning and memory of spatial information (4,5,6). Also, age-related changes in neuroanatomical, neurochemical and neurophysiological parameters of this structure of the brain have been well documented and causally linked to the etiology of memory impairment (5,7,8). This age-dependent impairment of spatial learning is strongly correlated with a deficit in the maintenance of neuronal activity long-term potentiation (LTP) in the hippocampus (9). LTP, a form of sy...

AI Technical Summary

Benefits of technology

We have also found that vulnerability to anaesthesia is partially antagonized by treatment with a cell membrane permeant calcium buffer to effect reversing aging potentiation of anaesthetic actions and to decrease the incidence of post-operative adverse events and clinically significant complications in elderly mammals, including human beings. We have found that aforesaid calcium buffers effect enhancement of anaesthetic requirements and a decrease in recovery time from anaesthesia.

It is an object of the present invention to provide methods of alleviating impaired mental function, particularly cognitively impaired mental function, memory loss and reducing recovery time in anaesthetized mammals, particularly aged mammals.

It is a further object to provide pharmaceutical compositions for use in said treatments of said mammals in vivo to alleviate impaired mental function, memory loss and reducing recovery time in anaesthetized mammals.

Without being bound by theory, we believe that the present invention relates to the consequences of increased levels of intracellular calcium during aging. We have found that BAPTA-AM ameliorated dysfunction on learning and memory of synaptic transmission caused by chronically raised Ca.sup.++ levels in aged brain slices. Decreasing intracellular free Ca.sup.++ levels in the brain of aged mammals enhanced this spatial learning and the retention of spatial information. The retention tests indicated a long lasting positive trend on the rats' spatial ability.

Accordingly, in a further aspect the invention provides a method of reducing the recovery time from anaesthesia for an aged mammal, said method comprising treating said mammal under said anaesthesia with a non-toxic, effective amount of a cell membrane permeant calcium buffer.

To effectively protect mammalian cells against impaired mental function, preferably, the effective amounts of Ca.sup.2+ buffer inside the cell should be in the concentration range of 10 .mu.M to 10 mM. This keeps intracellular calcium concentrations from rising to millimolar levels

Problems solved by technology

Accordingly, the age-dependent decrease in anaesthetic requirement is probably due to increased vulnerability of specific sites in the central nervous system to anaesthetic action.

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